The invention relates generally to the synthesis and use of molecules that contain a carbohydrate scaffold and an attached ring structure with various functional groups that are designed to meet some currently unmet medical needs and, more specifically to such molecules that are designed to have anti-bacterial, anti-fungal, anti-viral, anti-protozoal, or cytostatic or anti-tumor activities.
The medical community is constantly seeking new drugs with which to treat a variety of diseases, infections, and other health issues. Principal areas of focus include products which have anti-bacterial, anti-fungal, anti-viral, anti-protozoal, or anti-tumor activities. Each of these areas face challenges that could be met or alleviated by the new class of drugs that is the subject of the present application.
Anti-Bacterial Products
Although the anti-bacterial market includes many marketed products that are efficacious, increasing bacterial drug-resistance is driving a greater focus on the resistance profiles of new products under development. Resistant strains of serious infections are emerging that cannot be satisfactorily eradicated by currently marketed antibiotics. As early as half a century ago—just a few years after penicillin was put on the market—scientists began noticing the emergence of a penicillin-resistant strain of Staphylococcus aureus, a common bacterium that claims membership among the human body's normal bacterial flora. Resistant strains of gonorrhea, dysentery-causing shigella (a major cause of premature death in developing countries) and salmonella followed in the wake of staphylococcus 20 to 25 years later. Since then, the problem of antimicrobial resistance has become a serious public health concern with economic, social and political implications that are global in scope and cross all environmental and ethnic boundaries. Multi drug-resistant tuberculosis (MDR-TB) is no longer confined to any one country or to those co-infected with HIV, but has appeared in locations as diverse as eastern Europe, Africa and Asia among health care workers and in the general population. Penicillin-resistant pneumococci are likewise spreading rapidly, while resistant malaria is on the rise, disabling and killing millions of children and adults each year. In 1990, almost all cholera isolates gathered around New Delhi (India) were sensitive to cheap, first-line drugs furazolidone, ampicillin, co-trimoxazole and nalidixic acid. Now, 10 years later, formerly effective drugs are largely useless in the battle to contain cholera epidemics.
In some areas of the world—most notably South-East Asia—98% of all gonorrhoea cases are multi drug-resistant which in turn contributes to the sexual transmission of HIV. In India, 60% of all cases of visceral leishmaniasis—a sandfly-borne parasitic infection—no longer respond to an increasingly limited cache of first-line drugs; while in the industrialized world, as many as 60% of hospital-acquired infections are caused by drug-resistant microbes. These infections—the most recent of which are vancomycin-resistant Enterococcus (VRE) and methicillin-resistant Staphylococcus aureus (MRSA), are now no longer confined to hospital wards but have entered the community at large. So far, the only drug available to treat MRSA is vancomycin—itself faltering in the face of a renewed attack by vancomycin-intermediate Staphylococcus aureus, otherwise known as VISA.
Although most drugs are still active, the increasing incidence of resistance means that many of them may not be for long. In the case of tuberculosis, the emergence of multi drug-resistant bacteria means that medications that once cost as little as US$ 20 must now be replaced with drugs a hundred times more expensive. Other diseases are likewise becoming increasingly impervious as currently effective drugs continue to be underused by patients who do not complete courses, and misused through indiscriminate and over-prescribing.
Researchers soon discovered that pathogens develop resistance to antimicrobials through a process known as natural selection. When a microbial population is exposed to an antibiotic, more susceptible organisms will succumb, leaving behind only those resistant to the antimicrobial onslaught. These organisms can then either pass on their resistance genes to their offspring by replication, or to other related bacteria through “conjugation” whereby plasmids carrying the genes “jump” from one organism to another. This process is a natural, unstoppable phenomenon exacerbated by the abuse, overuse and misuse of antimicrobials in the treatment of human illness and in animal husbandry, aquaculture and agriculture. Disease—and therefore resistance—also thrives in conditions of civil unrest, poverty, mass migration and environmental degradation where large numbers of people are exposed to infectious diseases with little in the way of the most basic health care.
Methicillin-resistant Staphylococcus aureus (MRSA) micro-organisms quickly appeared after the introduction of isoxazolyl antibiotics like; methicillin, oxacillin, and cloxacillin. They became a nosocomial problem at the end of the 1980's, with a peak in the period 1993–1995. Recently another increase in MRSA infection was noticed; about 30% of the isolated S. aureus species were methicillin resistant. These resistance properties were not limited to the methicillin group only; a lot of S. aureus were often resistant to several antibiotics with only the glycopeptides remaining e.g. vancomycin and teicopanine.
The increasing number of anti-biotic resistant gram-positive organisms has reached epidemic proportions in hospitals; up to 40% of the staphylococci were methicillin (oxacillin resistant). Among all hospitals the incidence of MRSA rose from 2.4% in 1975 to 29% in 1991. In many nursing homes and chronic care facilities, the rate of MRSA colonization exceeds 50%.
The most disturbing recent trend in nosocomial infections has been the emergence of vancomycin-resistant enterococci (VRE). These bacteria were nonexistent in the U.S. until 1989 and now account for nearly 10% of the enterococci isolated from hospitalized patients. For many isolates of VRE there is no effective therapy. VRE can be spread from patient to patient and have the propensity to survive for prolonged periods on hands and environmental surfaces. The concern is that this resistance may be transferred to organisms such as Staphylococcus aureus and Clostridium difficile, which are even greater pathogenic potential to less compromised patients.
Anti-Fungal Products
In the field of fungal infections, there are two primary diseases, superficial and systemic diseases. Although historically the smaller of the two anti-fungal markets, systemic diseases are emerging as a key area within anti-infectives and is set to expand in terms of both market size and patient potential over the next several years. Systemic fungal infections are opportunistic, affecting immuno-compromised patients with HIV and those undergoing cytoxic therapy and transplant operations. They are commonly fatal, and almost always highly debilitating to the sufferer, affecting a number of organs and proving challenging to treat. Of patients treated for aspergillosis in 1999, 90% did not respond to drug therapy, and over 50% of these died due to the infection.
Anti-Viral Products
In the area of viral infections, the report focuses on herpes, influenza, human papillomavirus, rhinovirus and respiratory syncytial virus. Although over 70% of R&D in the area of anti-virals occurs in the treatment of HIV and hepatitis, these are also markets with substantial opportunity, and ones undergoing change. The emergence of cytokines and immunomodulatory drugs in the treatment of these infections is heralding a new era of treatment, and is set to revolutionize the structure of the market. The possibility of curative anti-viral therapy in the treatment of influenza and rhinovirus, the common cold, is drawing closer, and companies are beginning to realize the substantial potential that exists in these underserved markets. These areas are, with the exception of HIV and hepatitis, the anti-virals within which change is currently most apparent, and within which the principal new anti-viral drugs are emerging.
Cytomegalovirus Infection: (Cytomegalic Inclusion Disease)
Various infections caused by cytomegalovirus, occurring congenitally, postnatally, or at any age, ranging from inconsequential silent infection to disease manifested by fever, hepatitis, pneumonitis, and, in newborns, severe brain damage, stillbirth, or perinatal death.
Transmission of cytomegalovirus (CMV) is through blood, body fluids, or transplanted organs. Infection may be acquired transplacentally or during birth. Cytomegalic inclusion disease refers to the intranuclear inclusions found in enlarged infected cells. Prevalence in the general population increases gradually with age; 60 to 90% of adults have had CMV infection. Lower socio-economic groups tend to have a higher prevalence.
Congenital infection may be manifested only by cytomegaloviruria in an otherwise apparently normal infant. At the other extreme, CMV infection may cause abortion, stillbirth, or postnatal death from hemorrhage, anemia, or extensive hepatic or CNS damage.
Acquired infections are often asymptomatic, whether acquired postnatally or later in life. An acute febrile illness, termed cytomegalovirus mononucleosis or cytomegalovirus hepatitis, may occur.
In immunosuppressed patients, CMV is a major cause of morbidity and mortality. Disease often results from reactivation of latent virus infection. Patients may have pulmonary, GI, or CNS involvement. In the terminal phase of AIDS, CMV infection commonly causes retinitis and ulcerative disease of the colon or esophagus.
Postperfusion/posttransfusion syndrome can develop in a normal host 2 to 4 wk after transfusion with fresh blood containing CMV. It is characterized by fever lasting 2 to 3 wk, hepatitis of variable degree, splenomegaly, and a characteristic a typical lymphocytosis resembling that of infectious mononucleosis. Disease generally resembles spontaneous CMV mononucleosis, although splenomegaly is more common.
Products used up to now to treat CMV infections, are nucleoside analogs such as DHPG (ganciclovir) and (S)-HPMPC:

After some time, resistance is been built up against these products. Since the described products are no nucleoside analogs, it is highly possible that a different mechanism is followed to stop the virus. This makes the products interesting for treating (nucleoside resistant) CMV viruses. Moreover our identified anti-CMV products seem to be selectively active against CMV, and not against other viruses, bacteria, fungi or cancer cell lines. Such selectivity is highly demanded for pharmaceutical purposes.
Additional disadvantages of molecules such as DHPG and HPMPC are toxicity (DHPG) and difficulties to enter the cell for polar structures (HPMPC).
Herpes Zoster: (Shingles; Zona; Acute Posterior Ganglionitis)
An infection with varicella-zoster virus primarily involving the dorsal root ganglia and characterized by vesicular eruption and neuralgic pain in the dermatome of the affected root ganglia.
Herpes zoster is caused by varicella-zoster virus, the same virus that causes chickenpox. Herpes zoster occurs when the virus is reactivated from its latent state in the posterior root ganglia. Inflammatory changes occur in the sensory root ganglia and in the skin of the associated dermatome. The inflammation sometimes involves the posterior and anterior horns of the gray matter, the meninges, and the dorsal and ventral roots. Herpes zoster frequently occurs in HIV-infected patients and is more severe in immunosuppressed patients.
Geniculate zoster (Ramsay Hunt's syndrome) results from involvement of the geniculate ganglion. Pain in the ear and facial paralysis occur on the involved side. A vesicular eruption occurs in the external auditory canal, and taste may be lost in the anterior two thirds of the tongue.
Ophthalmic herpes zoster follows involvement of the gasserian ganglion, with pain and a vesicular eruption in the distribution of the ophthalmic division of the 5th nerve. Vesicles on the tip of the nose indicate involvement of the nasociliary branch of the 5th nerve and may predict the occurrence of corneal lesions. However, eye involvement may occur in the absence of lesions on the tip of the nose. An ophthalmologist should be consulted to help evaluate and prevent invasive eye disease.
Anti-Tumor Products
Cancer risk has changed over time. Some once common cancers have become rare. For example, cancer of the stomach was four times more prevalent in the United States in 1930 than it is today, probably because people today consume much less smoked, pickled, and spoiled food. On the other hand, lung cancer occurrence in the United States increased from 5 people per 100,000 in 1930 to 114 people per 100,000 in 1990, and the rate of lung cancer in women has skyrocketed. These changes are almost certainly the result of increased cigarette smoking. Cigarette smoking has also led to an increase in cancers of the mouth.
Age is an important factor in the development of cancer. Some cancers, such as Wilms' tumor, acute lymphocytic leukemia, and Burkitt's lymphoma, occur almost exclusively in young people. Why these cancers occur in the young is not well understood, but genetic predisposition is one factor. However, most cancers are more common in older people. Many cancers, including those of the prostate, stomach, and colon, are most likely to occur after age 60. Over 60 percent of the cancers diagnosed in the United States are in people over 65 years of age. Overall, the risk of developing cancer in the United States doubles every 5 years after age 25. The increased cancer rate is probably a combination of increased and prolonged exposure to carcinogens and weakening of the body's immune system, all associated with a longer life span
Cancer cells develop from normal cells in a complex process called transformation. The first step in the process is initiation, in which a change in the cell's genetic material primes the cell to become cancerous. An agent called a carcinogen such as a chemical, virus, radiation, or sunlight brings about the change in the cell's genetic material. However, not all cells are equally susceptible to carcinogens. A genetic flaw in the cell or another agent, called a promoter, may make it more susceptible. Even chronic physical irritation may make cells more susceptible to becoming cancerous. In the next step, promotion, a cell that has been initiated becomes cancerous. Promotion has no effect on non-initiated cells. Thus, several factors, often the combination of a susceptible cell and a carcinogen, are needed to cause cancer.
While many drugs have demonstrated anti-tumor activities, new, more effective drugs are constantly being sought.
Anti-Protozoal Products
Malaria is by far the world's most important tropical parasitic disease, and kills more people than any other communicable disease except tuberculosis. In many developing countries, and in Africa especially, malaria exacts an enormous toll in lives, in medical costs, and in days of labour lost. The causative agents in humans are four species of Plasmodium protozoa (single-celled parasites)—P.falciparum, P.vivax, P.ovale and P.malariae. Of these, P.falciparum accounts for the majority of infections and is the most lethal. Malaria is a curable disease if promptly diagnosed and adequately treated.
The need exists for new compounds that have anti-bacterial, anti-fungal, anti-viral, anti-protozoal, or anti-tumor activities.